Caspofungin acetate for injection is an echinocandin antifungal indicated in adults and pediatric patients (3 months of age and older) for:
Empirical therapy for presumed fungal infections in febrile, neutropenic patients. ( 1 )
Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. ( 1 )
Treatment of esophageal candidiasis. ( 1 )
Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies. ( 1 )
1.1Empirical Therapy for Presumed Fungal Infections in Febrile, Neutropenic Patients
Caspofungin acetate for injection is indicated as empirical therapy for presumed fungal infections in febrile, neutropenic adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.1 , 14.5 )] .
1.2Treatment of Candidemia and Other Candida Infections
Caspofungin acetate for injection is indicated for the treatment of candidemia and the following candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.2 , 14.5 )] . Limitations of Use : Caspofungin acetate for injection has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida .
1.3Treatment of Esophageal Candidiasis
Caspofungin acetate for injection is indicated for the treatment of esophageal candidiasis in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.3 , 14.5 )] . Limitations of Use : Caspofungin acetate for injection has not been approved for the treatment of oropharyngeal candidiasis (OPC). In the study that evaluated the efficacy of caspofungin in the treatment of esophageal candidiasis, patients with concomitant OPC had higher relapse rate of the OPC [see Clinical Studies ( 14.3 )] .
1.4 Treatment of Invasive Aspergillosis in Patients Who Are Refractory to or Intolerant of Other Therapies Caspofungin acetate for injection is indicated for the treatment of invasive aspergillosis in adult and pediatric patients (3 months of age and older) who are refractory to or intolerant of other therapies [see Clinical Studies ( 14.4 , 14.5 )] . Limitations of Use : Caspofungin acetate for injection has not been studied as initial therapy for invasive aspergillosis.
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Caspofungin is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to any component of this product [see Adverse Reactions ( 6 )] .
Caspofungin is contraindicated in patients with known hypersensitivity to any component of this product. ( 4 )
Warnings and precautions
Hypersensitivity : Anaphylaxis, possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm, and cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with use of caspofungin. Discontinue caspofungin at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment. ( 5.1 )
Hepatic Effects : Can cause abnormalities in liver enzymes. Isolated cases of hepatic dysfunction, hepatitis, or hepatic failure have been reported. Monitor patients who develop abnormal liver enzymes for evidence of worsening hepatic function, and evaluate risk/benefit of continuing caspofungin. ( 5.2 )
Elevated Liver Enzymes During Concomitant Use with Cyclosporine : Limit use to patients for whom potential benefit outweighs potential risk. Monitor patients who develop abnormal liver function tests (LFTs) during concomitant use with caspofungin. ( 5.3 )
5.1Hypersensitivity Anaphylaxis
and other hypersensitivity reactions have been reported during administration of caspofungin. Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with a fatal outcome, have been reported with use of caspofungin [see Adverse Reactions ( 6.2 )] .
Discontinue caspofungin at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment.
5.2Hepatic Effects
Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with caspofungin. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to caspofungin has not been established.
Monitor patients who develop abnormal liver function tests during caspofungin therapy for evidence of worsening hepatic function and evaluated for risk/benefit of continuing caspofungin therapy.
5.3Elevated Liver Enzymes During Concomitant Use With Cyclosporine
Elevated liver enzymes have occurred in patients receiving caspofungin and cyclosporine concomitantly. Only use caspofungin and cyclosporine in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver enzymes during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated.
Interactions
Cyclosporine : In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin. Caspofungin did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin and cyclosporine were co-administered. Monitor patients who develop abnormal liver enzymes during concomitant therapy and evaluate the risk/benefit of continuing therapy [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )] .
Tacrolimus : For patients receiving caspofungin and tacrolimus, standard monitoring of tacrolimus trough whole blood concentrations and appropriate tacrolimus dosage adjustments are recommended. Inducers of Hepatic CYP Enzymes Rifampin: Rifampin is a potent CYP3A4 inducer and concomitant administration with caspofungin is expected to reduce the plasma concentrations of caspofungin. Therefore, adult patients on rifampin should receive 70 mg of caspofungin daily and pediatric patients on rifampin should receive 70 mg/m 2 of caspofungin daily (not to exceed an actual daily dose of 70 mg) [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] .
Other Inducers of Hepatic CYP Enzymes Adults: When caspofungin is co-administered to adult patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg of caspofungin should be considered [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . Pediatric Patients : When caspofungin is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg/m 2 caspofungin (not to exceed an actual daily dose of 70 mg) should be considered [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] .
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on animal data, caspofungin may cause fetal harm (see Data) . There are insufficient human data to establish whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with caspofungin use in pregnant women. In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased peri-implantation loss, and incomplete ossification at multiple fetal sites when administered intravenously to pregnant rats and rabbits during organogenesis at doses up to 0.8 and 2 times the clinical dose, respectively (see Data) .
Advise patients of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data Animal Data In animal reproduction studies, pregnant rats dosed intravenously with caspofungin during organogenesis (gestational days [GD] 6 to 20) at 0.5, 2, or 5 mg/kg/day (up to 0.8 times the clinical dose based on body surface area comparison) showed increased resorptions and peri-implantation losses at 5 mg/kg/day. Incomplete ossification of the skull and torso and increased incidences of cervical rib were noted in offspring born to pregnant rats treated at doses up to 5 mg/kg/day.
In pregnant rabbits treated with intravenous caspofungin during organogenesis (GD 7 to 20) at doses of 1, 3, or 6 mg/kg/day (approximately 2 times the clinical dose based on body surface area comparison), increased fetal resorptions and increased incidence of incomplete ossification of the talus/calcaneus in offspring were observed at the highest dose tested. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma.
In peri- and postnatal development study in rats, intravenous caspofungin administered at 0.5, 2 or 5 mg/kg/day from Day 6 of gestation through Day 20 of lactation was not associated with any adverse effects on reproductive performance or subsequent development of first generation (F1) offspring or malformations in second generation (F2) offspring.
Adverse reactions
The following serious adverse reactions are discussed in detail in another section of the labeling:
Hypersensitivity [see Warnings and Precautions ( 5.1 )]
Hepatic Effects [see Warnings and Precautions ( 5.2 )]
Elevated Liver Enzymes During Concomitant Use with Cyclosporine [see Warnings and Precautions ( 5.3 )]
Adults : Most common adverse reactions (incidence 10% or greater) are diarrhea, pyrexia, ALT/AST increased, blood alkaline phosphatase increased, and blood potassium decreased. ( 6.1 )
Pediatric Patients : Most common adverse reactions (incidence ≥10%) are pyrexia, diarrhea, rash, ALT/AST increased, blood potassium decreased, hypotension, and chills. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-9994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of caspofungin cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults The overall safety of caspofungin was assessed in 1865 adult individuals who received single or multiple doses of caspofungin: 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 patients with invasive aspergillosis; and 394 individuals in phase I studies.
In the empirical therapy study patients had undergone hematopoietic stem-cell transplantation or chemotherapy. In the studies involving patients with documented Candida infections, the majority of the patients had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus studies often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications.
Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients In the randomized, double-blinded empirical therapy study, patients received either caspofungin 50 mg/day (following a 70 mg loading dose) or AmBisome ® (amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the caspofungin and AmBisome groups, respectively.
Also reported was an isolated, serious adverse reaction of hyperbilirubinemia. Adverse reactions occurring in 7.5% or greater of the patients in either treatment group are presented in Table 2. Table 2: Adverse Reactions Among Patients with Persistent Fever and Neutropenia Incidence 7.5% or greater for at Least One Treatment Group Adverse Reactions Caspofungin * N=564 (%) AmBisome † N=547 (%) All Systems, Any Adverse Reaction 95 97 Investigations 58 63 Alanine Aminotransferase Increased 18 20 Blood Alkaline Phosphatase Increased 15 23 Blood Potassium Decreased 15 23 Aspartate Aminotransferase Increased 14 17 Blood Bilirubin Increased 10 14 Blood Magnesium Decreased 7 9 Blood Glucose Increased 6 9 Bilirubin Conjugated Increased 5 9 Blood Urea Increased 4 8 Blood Creatinine Increased 3 11 General Disorders and Administration Site Conditions 57 63 Pyrexia 27 29 Chills 23 31 Edema Peripheral 11 12 Mucosal Inflammation 6 8 Gastrointestinal Disorders 50 55 Diarrhea 20 16 Nausea 11 20 Abdominal Pain 9 11 Vomiting 9 17 Respiratory, Thoracic and Mediastinal Disorders 47 49 Dyspnea 9 10 Skin and Subcutaneous Tissue Disorders 42 37 Rash 16 14 Nervous System Disorders 25 27 Headache 11 12 Metabolism and Nutrition Disorders 21 24 Hypokalemia 6 8 Vascular Disorders 20 23 Hypotension 6 10 Cardiac Disorders 16 19 Tachycardia 7 9 Within any system organ class, individuals may experience more than 1 adverse reaction. * 70 mg on Day 1, then 50 mg once daily for the remainder of treatment; daily dose was increased to 70 mg for 73 patients. † 3 mg/kg/day; daily dose was increased to 5 mg/kg for 74 patients.
The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with caspofungin (35%) than in the group treated with AmBisome (52%).
To evaluate the effect of caspofungin and AmBisome on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of greater than or equal to 1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. Among patients whose baseline creatinine clearance was greater than 30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin (3%) than in the group treated with AmBisome (12%).
Candidemia and Other Candida Infections In the randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70 mg loading dose) or amphotericin B 0.6 to 1 mg/kg/day. Adverse reactions occurring in 10% or greater of the patients in either treatment group are presented in Table 3. Table 3: Adverse Reactions Among Patients with Candidemia or Other Candida Infections* Incidence 10% or Greater for at Least One Treatment Group Adverse Reactions Caspofungin 50 mg † N=114 (%) Amphotericin B N=125 (%) All Systems, Any Adverse Reaction 96 99 Investigations 67 82 Blood Potassium Decreased 23 32 Blood Alkaline Phosphatase Increased 21 32 Hemoglobin Decreased 18 23 Alanine Aminotransferase Increased 16 15 Aspartate Aminotransferase Increased 16 14 Blood Bilirubin Increased 13 17 Hematocrit Decreased 13 18 Blood Creatinine Increased 11 28 Red Blood Cells Urine Positive 10 10 Blood Urea Increased 9 23 Bilirubin Conjugated Increased 8 14 Gastrointestinal Disorders 49 53 Vomiting 17 16 Diarrhea 14 10 Nausea 9 17 General Disorders and Administration Site Conditions 47 63 Pyrexia 13 33 Edema Peripheral 11 12 Chills 9 30 Respiratory, Thoracic and Mediastinal Disorders 40 54 Tachypnea 1 11 Cardiac Disorders 26 34 Tachycardia 8 12 Skin and Subcutaneous Tissue Disorders 25 28 Rash 4 10 Vascular Disorders 25 38 Hypotension 10 16 Blood and Lymphatic System Disorders 15 13 Anemia 11 9 Within any system organ class, individuals may experience more than 1 adverse reaction. * Intra-abdominal abscesses, peritonitis and pleural space infections. † Patients received caspofungin 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment.
The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with caspofungin (20%) than in the group treated with amphotericin B (49%).
To evaluate the effect of caspofungin and amphotericin B on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of greater than or equal to 1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. In a subgroup of patients whose baseline creatinine clearance was greater than 30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin than in the group treated with amphotericin B.
In a second randomized, double-blinded invasi
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Composition
Active ingredients
CASPOFUNGIN ACETATE 70MG/VIAL
Strengths and forms
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